Preclinical features of familial FTD

Background Up to 40% of frontotemporal dementia (FTD) cases carry an autosomal dominant mutation, the majority in the progranulin ( GRN ), microtubule‐associated protein tau ( MAPT ) or chromosome 9 open reading frame 72 ( C9orf72 ) genes. Familial FTD offers a unique window for observing the earliest disease‐related changes, as mutation carriers can be identified in their presymptomatic stages. Method We performed a systematic review of discoveries from major European prospective longitudinal cohorts of presymptomatic mutation carriers, particularly the Rotterdam FTD Risk Cohort (FTD‐RisC) and the GENetic Frontotemporal dementia Initiative (GENFI). Result In the last 10 years, biomarker changes that begin many years before symptom onset have been identified. Presymptomatic neuropsychological assessment have demonstrated executive dysfunction as a common feature of all the genetic groups, as well as mutation‐specific patterns in GRN (memory), MAPT (language) and C9orf72 (attention). Grey matter atrophy and hypometabolism appear around 10 years prior to symptom onset. White matter tract abnormalities signify the first disease‐related changes, seen as early as three decades before symptom onset, again with mutation‐specific patterns in GRN (internal capsule), MAPT (uncinate fasciculus) and C9orf72 (posterior tracts). Several fluid biomarker candidates have been identified. Neurofilament light chain provides a reliable measure of disease staging, progression and survival, with levels being highest in C9orf72 ‐associated ALS and lowest in MAPT mutation carriers. Two of the biggest challenges are identifying and conceptualizing the transitional (conversion) stage between presymptomatic and overt disease, similar to mild cognitive impairment in the evolution to Alzheimer’s Disease dementia, and the use of estimated years to symptom onset as a proxy for actual symptom onset—which varies widely between and within families and across mutations. Conversion seems to be a relatively rapid process, and there are no clinical tools to capture this transition. There is also a lack of reliable disease‐staging markers. Conclusion The pathological heterogeneity in FTD warrants a multimodal approach, and future challenges lie in finding sensitive clinical markers that are able to identify the earliest cognitive and behavioural features, as well as neuroimaging and fluid biomarkers that can reliably differentiate between clinical and pathological FTD subtypes.